title: Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression.
abstract: OBJECTIVE
  To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC).
  
  
  METHODS
  PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated.
  
  
  RESULTS
  PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI)  = 0.42-0.84, p = 0.004), and 0.73 (95%CI = 0.55-0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39-0.82, p = 0.003) and 0.72 (95%CI 0.54-0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43-0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41-0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth.
  
  
  CONCLUSIONS
  Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Clinical Research Coordination, Instituto Nacional de Câncer (INCA)-Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Brait
authors.forename: Leonel
authors.initials: L
authors.lastname: Maldonado
authors.forename: Maartje G
authors.initials: MG
authors.lastname: Noordhuis
authors.forename: Maartje
authors.initials: M
authors.lastname: Noordhuis
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Begum
authors.forename: Myriam
authors.initials: M
authors.lastname: Loyo
authors.forename: Maria Luana
authors.initials: ML
authors.lastname: Poeta
authors.forename: Alvaro
authors.initials: A
authors.lastname: Barbosa
authors.forename: Vito M
authors.initials: VM
authors.lastname: Fazio
authors.forename: Roberto
authors.initials: R
authors.lastname: Angioli
authors.forename: Carla
authors.initials: C
authors.lastname: Rabitti
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Pauline
authors.initials: P
authors.lastname: de Graeff
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: G Bea A
authors.initials: GB
authors.lastname: Wisman
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Mohammad O
authors.initials: MO
authors.lastname: Hoque
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D015331:Cohort Studies; D019175:DNA Methylation; D017931:DNA Primers; D000077209:Decitabine; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: D017931:DNA Primers; D009414:Nerve Growth Factors; C482860:UCHL1 protein, human; C510637:VGF protein, human; D000077209:Decitabine; D043222:Ubiquitin Thiolesterase; D001374:Azacitidine